Glycolysis and gluconeogenesis (short map)

Glycolysis and gluconeogenesis (short map)

D-Glucose is the major energy source for mammalian cells as well as an important substrate for protein and lipid synthesis. Mammalian cells take up D-Glucose from extracellular fluid into the cell through two families of structurally related glucose transporters. Solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT4) is one such transporters. It mediates bidirectional and energy-independent process of glucose transport in most tissues and cells [1], [2].

The first step of D-Glucose conversion is its immediate phosphorylation to alpha-D-Glucose-6-phosphate by the family of hexokinases: Hexokinase 1 (HXK1) [3], [4], [5], Hexokinase 2 (HXK2) [3], [6], Hexokinase 3 (HXK3) [3], [7], and Glucokinase (hexokinase 4) HXK4 [3], [8]. The reverse reaction takes place in gluconeogenesis and plays a crucial role in maintaining D-Glucose homeostasis. Solute carrier family 37 (glucose-6-phosphate transporter), member 4 (G6PT1) translocates alpha-D-Glucose-6-phosphate from the cytoplasm into the lumen of the endoplasmic reticulum [9], [10] where Glucose-6-phosphatase, catalytic subunit (G6PT) hydrolyses the alpha-D-Glucose-6-phosphate into D-Glucose and phosphate [10], [11].

Alpha-D-Glucose-6-phosphate is further converted to Beta-D-Fructose 6-phosphate by Glucose phosphate isomerase (GPI) [12], [13], [14]. Then, phosphofructokinases (Phosphofructokinase, muscle - PFKM, Phosphofructokinase, platelet - PFKP, Phosphofructokinase, liver - PFKL) attach the second phosphate group to Beta-D-Fructose 6-phosphate resulting in formation of Beta-D-Fructose 1,6-bisphosphate [15], [16], [17]. Beta-D-Fructose 1,6-bisphosphate is further hydrolyzed by important gluconeogenic enzymes Fructose-1,6-bisphosphatase 1 (F16P) and Fructose-1,6-bisphosphatase 2 (F16Q) to Beta-D-Fructose 6-phosphate and phosphate [18], [19].

Vertebrate aldolases exist as three isozymes with different tissue distributions and kinetics: Aldolase A, fructose-bisphosphate (ALDOA) (muscle and red blood cell), Aldolase B, fructose-bisphosphate (ALDOB) (liver, kidney, and small intestine), and Aldolase C fructose-bisphosphate (ALDOC) (brain and neuronal tissue). These are ubiquitous enzymes that catalyze the reversible aldol cleavage of Beta-D-Fructose 1,6-bisphosphate (and also D-Fructose-1-phosphate) to Dihydroxyacetone phosphate and either (D)-Glyceraldehyde 3-phosphate or Glyceraldehyde, respectively [20], [21], [22]. Dihydroxyacetone phosphate is further reversibly isomerized to (D)-Glyceraldehyde 3-phosphate by Triosephosphate isomerase 1 (TPI1) [23], [24].

(D)-Glyceraldehyde 3-phosphate is metabolized to 3-Phospho-(D)-glyceroyl phosphate by glyceraldehyde-3-phosphate dehydrogenases (G3P1, G3P2, G3PT) [25], [26], [27]. Enzymes Phosphoglycerate kinase 1 (PGK1), Phosphoglycerate kinase 2 (PGK2) catalyze the reversible transfer of a phosphoryl group from 3-Phospho-(D)-glyceroyl phosphate to ADP which results in formation of D-Glycerate 3-phosphate [28], [29], [30]. D-Glycerate 3-phosphate is enzymatically converted into 2-Phospho-(D)-glyceric acid by phosphoglycerate mutase that has several isoforms: Phosphoglycerate mutase 1 (brain) - PGAM1, Phosphoglycerate mutase 2 (muscle) - PGAM2, Phosphoglycerate mutase family 3 - PGAM3, and by a multifunctional enzyme 2,3-Bisphosphoglycerate mutase (PMGE) [31], [32], [33], [34], [35]. After releasing water, catalyzed by Enolase 1, (alpha), (ENO1), Enolase 3 (beta, muscle) (ENO3), Enolase 2 (gamma, neuronal) (ENO2) Phosphoenolpyruvate is formed [36], [37], [38]. Then it is converted to Pyruvic acid by Pyruvate kinase, liver and RBC (KPYR) [39], [40] and Pyruvate kinase, muscle (PKM2) [41], [42].

Pyruvate carboxylase (PYC) converts Pyruvic acid to 2-Oxo-succinic acid [43], [44] that is reversibly reduced by Malate dehydrogenase 1, NAD (soluble) (MDH1) and Malate dehydrogenase 2, NAD (mitochondrial) (MDH2) to (S)-Malic acid [45], [46], [47], [48]and is metabolized back to Phosphoenolpyruvate by Phosphoenolpyruvate carboxykinase 2 (mitochondrial) (PPCKM) [49], [50] and Phosphoenolpyruvate carboxykinase 1 (soluble) (PPCKC) [51], [52].

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